[Inhibition of hematopoiesis and osteoblast formation in the bone marrow of lethally irradiated mice following transplantation of allogeneic lymphocytes].
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Biomedical subjects
Publications and source records attributed to V N Shvets.
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BACKGROUND: Disturbances in the heart energy provision is important in the stress-induced injury of myocardium. In order to learn the causes of age-dependent differences in myocardial sensitivity to stress, we determined the level of adenylates, creatine and creatine phosphate in adult and old rat heart during an immobilization stress. METHODS: Fifty male Wistar rats were used to study the myocardial adenine nucleotides, creatine and creatine phosphate pool and creatine kinase activity during an immobilization period. RESULTS: The concentration of adenine nucleotides in old and adult rat hearts was similar. The total concentration of adenylate pool, ATP and ADP in the heart of both age groups was reduced during stress. However, in old rats under stress the concentration of ATP in a less measure and ADP in a greater measure is decreased against that observed in adult animals. The level of inorganic phosphate in old rat heart remains the same as in adult rats. CONCLUSION: The creatine kinase system may be important in stabilizing the ATP level in myocardium of adult rats during stress. The role of this system in heart energy metabolism during stress is decreased in old rats. Disturbances of isoenzyme creatine kinase activity are responsible for these disorders.
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The activity of the myofibrillar isoenzyme creatine phosphokinase (CPK) in the heart inhibits with age. This may be explained by impaired association of CPK with myofibrils. The immobilization stress led to a sharp fall in CPK activity in its decreased affinity to the substrate. Changes in the catalytic properties of myofibrillar CPK in the myocardium of adult stressed rats raise effectiveness of its function in altered cardiac metabolism in stress.
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Lipid peroxidation (LPO) in the heart of adult (10-12 month) and old (22-25 month) Wistar male rats was investigated during immobilized stress. Immobilization of rats was accompanied by increasing the concentration of all studied LPO intermediates in the myocardium of both age groups. Accumulation of LPO products in old rat hearts was considerably higher than in adult ones. Dimethyl sulfoxide injection limited stress-induced stimulation of LPO. There were age related variations in efficiency of this antioxidant effect on the heart during immobilized stress.
Male rats of the Wistar strain were for 40 days exposed to hypokinesia and hypodynamia. After exposure bone biochemical, physical, chemical, morphological and strength parameters were investigated. Both simulation studies led to changes in calcium and phosphorus metabolism but the nature of bone changes was different. It is concluded that the efficacy of drugs used as countermeasures in animal simulation experiments should be assessed by both exposures, viz. small size cages and suspension, because they reproduce different mechanisms of potential bone lesions in microgravity. It is also inferred that various countermeasures should be used in combination to yield the best results.
Oral administration of hydroxy-dimethyl aminopropylene biphosphonate (DMAP) at a dose of 0.5 mg/kg increased the volume density (mass) of trabecular bone in the tibial metaphysis of untreated rats and helped to maintain it at the normal level in hypokinetic rats. Oral administration of hydroxy-ethylidene biphosphonate (OEDP) at a dose of 20 mg/kg and vitamin 24,25(OH)2D3 at a dose of 1,25 micrograms did not induce any quantitative changes in bones of untreated or immobilized rats. The combined treatment with either biphosphonate and vitamin D3 exerted a similar effect as compared to that of biphosphonates used singly. During hypokinesia the total amount of osteoclasts declined. This effect was also seen in response to biphosphonates and vitamin D3. The two biphosphonates produced an opposite effect on the osteoclast population in untreated animals: it increased in response to OEDP and decreased in response to DMAP. In contrast to OEDP, low doses of DMAP can efficiently inhibit bone resorption upon various routes of its administration and can be viewed as a preventive and therapeutic drug in the case of osteoporosis.
During 35-day hypokinesia rat spongy bone in the tibia and vertebrae varied in two phases. The first phase (up to 15 days) was induced by a stress-reaction and the second phase by adaptation to hypokinesia. Under the influence of subcutaneous injections of hydroxydimethyl aminopropylidene biphosphonate (AMOK) at a dose of 0.01 mg/kg/day bone changes disappeared: throughout the study spongy bone mass remained as in controls. AMOK administration at a dose of 5 mg/kg/day 10 days prior to hypokinetic exposure did not eliminate its inhibitory effect although the initial bone mass was 1.5-2 times higher than in the controls. However at the adaptation phase (beginning with day 15) bone mass increased, reaching the baseline. This indicates a decline in bone sensitivity to muscle unloading. It is concluded that AMOK modifies bone responses to various hypokinetic factors.
The preventive effect of alpha-hydroxydimethyl-gamma-aminopropylidene bis-phosphonate was investigated histomorphometrically. The agent was injected subcutaneously to rats before hypokinesia at a dose of 5 mg/kg or during 35-day hypokinesia at a dose of 0.005 or 0.01 mg/kg daily. Regardless of the treatment protocol, the agent prevented osteoporosis and did not affect the epiphyseal growth plate. The agent modified significantly the bone cell count: osteoblasts decreased and osteoclasts increased. It is concluded that when compared to xydiphone (hydroxyethylidene bis-phosphoric acid), the agent proves several hundred times more effective. It is assumed that the agent modifies the relation between bone formation and bone resorption. Its osteotropic effect manifests as inhibition of bone resorption.
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The diphosphonate effect on bones was studied in Wistar male rats weighing about 200 g. The rats were kept for 60 days in small-size cages where their motor activity was diminished. Every day the rats were given per os 0.3% solution of 1-hydroxy-ethylene-1,1-diphosphonate (HEDP) containing 9 mg/kg phosphorus. In the course of hypokinetic exposure the rats developed generalized osteoporosis. Histomorphometric measurements demonstrated that the drug did not prevent mineral losses from the tubular bones (humerus, femur). However, the drug led to a complete bone mass recovery in the pelvic and a partial recovery in the sternum. The drug also produced a preventive effect on the population of cells-precursors of osteogenesis the number of which decreases significantly during hypokinesia.
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It was established by the method of the osteoclast prints prepared from a distal part of femur that osteoclasts are highly radioresistant cells with Do=8.35 Gy. The postirradiation study of the nuclei distribution and the osteoclast quantity showed that the histogenesis of young cell forms changed and the total number of osteoclasts decreased. This was probably connected with a change in the hormonal status of the exposed body or with the direct effect of radiation on cells-precursors of osteoclasts.
During 7 days prior to hypokinesia male Wistar rats were given 10 mg/kg xydiphone to ensure and additional bone pool. Then the rats were exposed to 32-day hypokinesia during which they were injected with 1 or 5 mg/kg xydiphone. Drug administration before hypokinesia prevented spongy bone losses in long bones, torso and pelvic bones. Xydiphone injections before and during hypokinesia not only prevented osteoporosis but also led to bone mass increase above the normal level. It is assumed that xydiphone stimulates the involvement of cells-precursors in the new bone formation. This method of osteoporosis prophylaxis can be recommended for space medicine application.
Wistar male rats weighing 250-270 g were exposed to hypokinesia for 7, 15, 35 or 60 days. Spongy bone of the metaphysis of long bones, vertebral body, breast bone and iliac bone were examined histomorphometrically. It was found that during hypokinesia osteoporosis developed in two stages: Stage 1 (from hypokinesia day 1 to day 15) was characterized by a drastic bone mass loss due to stress-effects (steroid osteopenia) and Stage 2 (from hypokinesia day 15 to the end) was characterized by adaptive changes which included steady-state development and transition to a lower functional level (immobilization osteoporosis).